Delayed tumor-draining lymph node irradiation preserves the efficacy of combined radiotherapy and immune checkpoint blockade in models of metastatic disease

Irma Telarovic, Carmen S. M. Yong, Lisa Kurz, Irene Vetrugno, Sabrina Reichl, Alba Sanchez Fernandez, Hung-Wei Cheng, Rona Winkler, Matthias Guckenberger, Anja Kipar, Burkhard Ludewig and Martin Pruschy ()
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Irma Telarovic: University of Zurich
Carmen S. M. Yong: University of Zurich
Lisa Kurz: Kantonsspital St. Gallen
Irene Vetrugno: University of Zurich
Sabrina Reichl: University of Zurich
Alba Sanchez Fernandez: University of Zurich
Hung-Wei Cheng: Kantonsspital St. Gallen
Rona Winkler: University of Zurich
Matthias Guckenberger: University of Zurich
Anja Kipar: Vetsuisse Faculty, University of Zurich
Burkhard Ludewig: Kantonsspital St. Gallen
Martin Pruschy: University of Zurich

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Cancer resistance to immune checkpoint inhibitors motivated investigations into leveraging the immunostimulatory properties of radiotherapy to overcome immune evasion and to improve treatment response. However, clinical benefits of radiotherapy-immunotherapy combinations have been modest. Routine concomitant tumor-draining lymph node irradiation (DLN IR) might be the culprit. As crucial sites for generating anti-tumor immunity, DLNs are indispensable for the in situ vaccination effect of radiotherapy. Simultaneously, DLN sparing is often not feasible due to metastatic spread. Using murine models of metastatic disease in female mice, here we demonstrate that delayed (adjuvant), but not neoadjuvant, DLN IR overcomes the detrimental effect of concomitant DLN IR on the efficacy of radio-immunotherapy. Moreover, we identify IR-induced disruption of the CCR7-CCL19/CCL21 homing axis as a key mechanism for the detrimental effect of DLN IR. Our study proposes delayed DLN IR as a strategy to maximize the efficacy of radio-immunotherapy across different tumor types and disease stages.

Date: 2024
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DOI: 10.1038/s41467-024-49873-y

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